DE69834195T2 - STABILIZED TRAMADOL FORMULATIONS WITH DELAYED RELEASE - Google Patents

Abstract

A stabilized sustained release oral solid dosage form which includes an effective amount of tramadol or a pharmaceutically acceptable salt thereof dispersed in a matrix of a hydrophobic material comprising a wax-like substance which was melted or softened during the preparation of the matrix, is cured at a temperature from about 35° C. to about 65° C. for a time period from about 4 to about 72 hours, such that the formulation, when subjected to in-vitro dissolution after exposure to accelerated storage conditions of at least one month at 40° C./75% RH, releases an amount of tramadol which does not vary at any given dissolution time point by more than about 20% of the total amount of tramadol released when compared to in-vitro dissolution conducted prior to subjecting the dosage form to the accelerated storage conditions.

Description

BACKGROUND THE INVENTION

The present invention meets matrix formulations of sustained release, the tramadol or a pharmaceutically acceptable salt thereof containing therapeutic agent.

preparations with delayed Release are known in the art to slow release of an active substance an extended one Achieve the duration of the effectiveness of the drug across from extended to conventional release becomes. Preferably holds such a preparation the drug concentration in the blood within of the therapeutic window for Upright for 12 hours or more.

One important aspect in the production, regulatory review and approval of all dosage forms concerns their stability over longer periods of time. The Stability data obtained with respect to a specific dosage form, directly affect their durability. The stability of a pharmaceutical dosage form based on their physical, chemical, microbiological, to maintain therapeutic and toxicological properties, when stored, that is, in a special container and Surroundings. Requirements for stability studies are e.g. in Good Manufacturing Practices (GMPs), U.S.P. as well as by the regulatory requirements of the country where the marketing authorization for a pharmaceutical form is to be obtained, covered. In the United States can apply for testing and optionally marketing an active ingredient or a drug formulation through a New Drug Application (NDA), a shortened New Drug Application ("abbreviated new drug application "(ANDA)) or an investigative New Drug Application (IND) become.

The Active substances used in prolonged release dosage forms used frequently particular problems in terms of their physical stability during the Storage on. For example, it is known that waxes which are in such Formulations are used when standing longer physical changes subject. Precautions can be made to waxes during stabilize the production or prevent the change happens. Fats and waxy materials are known to crystallize in unstable forms when in a purified state which uses unpredictable variations in availability rates while the stability tests at the time of manufacture and during later storage caused.

It is aware that certain strategies can be followed to in many cases to obtain stabilized sustained-release formulations, such as. ensure that the individual active ingredients in one stable form before being incorporated into the product and that the processing does not change this state, delay the instability by Lock in additional Additives and causes of the individual active substances of the dosage form, to achieve a stable state before the product is finally ready is placed.

It It has also been recognized that the moisture content of the product as well as the stability of the product. amendments in the liquid content a polymeric film, e.g. the ethylcellulose, the speed can the water permeation and the drug availability change. Likewise is It is known that binders such as Acacia are less soluble when exposed to moisture and heat are exposed. The moisture content of a product However, it can be successful by controlling the processing methods and proper packaging of the product.

hydrophobic Polymers such as certain cellulose derivatives, zein, acrylic resins, Waxes, higher aliphatic alcohols and polylactic acid and polyglycolic acids have been used in the art to form of administration with delayed To develop release. Method of using these polymers, by dosage forms with delayed To develop release, e.g. Tablets, capsules, suppositories, Spheroids, globules or microspheres, are the single unit of presentation with these to coat hydrophobic polymers ( "Overcoat"). It is in the Technique known that these hydrophobic coatings either from a solution, Suspension or dry can be applied. Because most of these Polymers have a low solubility in water, they are normally dissolved by dissolving the Polymer in an organic solvent and spraying the solution on an individual drug form (such as pellets or tablets) and Evaporation of the solvent applied.

The use of organic solvents in the manufacture of hydrophobic coatings is considered undesirable because of inherent problems with combustibility, carcino genicity, environmental concerns and safety in general. It is therefore highly desirable in the art to provide a sustained-release coating obtained from an aqueous dispersion of a hydrophobic material. Unfortunately, such formulations have been susceptible to changes in solubility characteristics during storage, making such formulations unsuitable as sustained release oral dosage forms containing therapeutic agents. Stabilized sustained-release formulations employing ethylcellulose as a sustained-release coating are described in prior U.S. Patent Nos. 5,273,760, 5,478,577, and 5,472,712.

stabilized Delayed formulations Release containing one or more acrylic acid polymers as a coating with delayed Release are described in the earlier U.S. patents No. 5,286,493; 5,580,578 and 5,639,476 of the Applicant.

oral Dosage forms with delayed Release in which the therapeutic agent is in a matrix which is one or more hydrophobic and / or hydrophilic Contains materials, are also well known to those skilled in the art. In this regard is on U.S. Patent No. 3,965,256 (Leslie), which is directed to a pharmaceutical company Composition with slow release is addressed, the one Combination of a higher aliphatic alcohol and a hydrated hydroxyalkyl cellulose includes; and U.S. Patent Nos. 4,861,598 and 4,970,075 (Oshlack et al.), wherein the release of the therapeutic agent on a Base delayed Release by using a combination of a higher aliphatic Alcohol and an acrylic resin extended as base material becomes.

Schmelzgranulationstechniken have also been proposed for sustained release formulation provide. Melt granulation normally closes the mechanical one Processing of a drug in particulate form with one or more suitable binders and / or pharmaceutically acceptable excipients in a mixer until one or more of the binders melt and on the surface glue the particle and finally Form granules. This technique has been applied in the Examples of sustained-release oral tramadol dosage forms, which is carried out in Applicant's U.S. Patent No. 5,591,452.

The International publication WO 92/06679 discloses melt granulation processes for the production of pellets containing therapeutic active substances. The Procedure closes the mechanical processing of a mixture containing the active substance contains in cohesive Mold with a binder having a melting point of 40-100 ° C, while enough Energy is provided for melting the binder and with Moisture-coated ("overmoist") spherical pellets formed and thereby an additional cohesive substance is added, while the mechanical processing is continued to dry eventually To get pellets.

The International publication WO 93/18753 also discloses further melt extrusion processes for the production of sustained release pellets. This Procedure closes pelletizing a mixture containing an active ingredient in fine distributed form and a binder containing one or more water-insoluble, Wax-like binder substances having a melting point above from 40 ° C using a high shear mixer.

Task and Summary of the invention

It It is an object of the present invention to provide an oral solid dosage forms with delayed release of tramadol which is stable for at least 12 hours (e.g. up to twenty-four hours) Administration is suitable for the treatment of pain.

It It is an object of the present invention to provide tramadol formulations with delayed To provide release which provides stable release, even after the exposure accelerated storage conditions or prolonged storage at room temperature.

It It is an object of the present invention to provide a process for the preparation one tablet with delayed To provide release which includes tramadol as the active ingredient, wherein the tablet provides a stable release profile of the active agent, when placed in a use environment, despite the suspension across from accelerated storage conditions.

An object of the present invention is to provide a stabilized tramadol formulation with delay in sustained release, wherein the sustained release is provided by a matrix of a hydrophobic material comprising a waxy substance and the active agent, wherein the waxy substance is softened or melted during preparation of the matrix, and wherein the formulation provides stable release of the matrix Drug contained in the formulation, despite being exposed to accelerated storage conditions, may be considered acceptable in terms of expiration dates by state regulatory agencies such as the US Food and Drug Administration ("FDA").

It Another object of the present invention is a method for the preparation of a sustained-release tramadol tablet, which contains a hydrophobic material which is a waxy one Substance includes, so that it has a stable release profile of Tramadol exhibits when placed in the use environment will face, despite the suspension accelerated storage conditions.

These further objects have been achieved by the present invention, which u.a. a stabilized solid oral dosage form with delayed Release or formulations concerns, the tramadol or a pharmaceutically acceptable salt or a complex thereof in one Matrix containing a hydrophobic material which while softens or melts the preparation of the dosage form, wherein the dosage form after the preparation of the matrix, the tramadol contains at a suitable temperature (e.g., a temperature above the glass transition temperature of the hydrophobic material (in the case of the polymer)) to an endpoint is reached, at which the hardened Dosage form when subjected to in vitro release which releases tramadol in quantities that are not given to any Time along the release curve by more than about 20% of the amount of tramadol that is released when it compared with the in vitro release of the formulation before curing becomes.

The The invention is further directed to a stabilized solid oral Form of administration with delayed release containing tramadol as an active ingredient, comprising an effective amount Tramadol or a pharmaceutically acceptable salt thereof dispersed in a matrix of a hydrophobic material comprising a waxy one Substance which during melted or softened the preparation of the matrix. The solid Dosage form is cured at a sufficient temperature and for one sufficient time so that an end point is reached at which the solid dosage form provides a stable release profile. Of the End point is determined by comparing the release profile the solid dosage form directly after curing, with the release profile the solid dosage form after exposure to accelerated Storage conditions for at least one month at 40 ° C and 75% relative humidity. The curing is preferred in one Temperature of 35 ° C up to 65 ° C, preferably from 40 ° C up to 60 ° C, preferred for a period of 4 to 72 hours. In certain preferred embodiments will harden preferred for a period of about 24 hours or more, carried out until the endpoint is reached. In certain embodiments, curing is performed at a temperature of 45 ° C up to 55 ° C for one Period of 4 to 72 hours, preferably for a period of 24 hours, until the end point is reached. The waxy substance can be selected from the group consisting of hydrogenated vegetable oil, hydrogenated Castor oil, Paraffin, higher aliphatic alcohols, higher aliphatic acids, long-chain fatty acids, Fettsäureestern and mixtures thereof. The hydrophobic material may further include hydrophobic polymer comprise - selected from the group consisting of acrylic acid polymers, alkylcelluloses and mixtures thereof. Furthermore, the matrix may be a hydrophilic polymer, e.g. a cellulose ether or other hydrophilic material. The dosage forms with delayed Release may take the form of a unit dose of multiparticulates or a tablet available.

In certain preferred embodiments comprises the matrix of the stabilized oral solid dosage form with delayed Release tramadol, a higher aliphatic alcohol and a hydrophobic polymer selected from the group consisting of acrylic acid polymers, alkylcelluloses and mixtures thereof. In further preferred embodiments includes the matrix of the stabilized oral dosage form with delayed Release tramadol and hydrogenated vegetable oil.

Another aspect of the invention provides a process for the preparation of a sustained-release oral solid dosage form containing tramadol as the active ingredient. This method involves mixing tramadol together with a hydrophobic material and an optional binder to form a homogeneous mixture, then heating the mixture and then extruding and granulating the mixture. Thereafter, the granules are preferably pressed into tablets (after mixing with optional pharmaceutical excipients such as talc and a lubricant such as magnesium stearate) and the tablet is cured as described herein. In alternative embodiments, the granules (or the Extrudate cut into particles of suitable size) as described herein, and then the granules are divided into suitable dosage units of tramadol (eg filled into pharmaceutically acceptable gelatin capsules). In preferred embodiments, the curing is carried out at a temperature of from 35 ° C to 65 ° C, preferably from 40 ° C to 60 ° C for a period of from 4 to 72 hours, preferably at least 24 hours. In further preferred embodiments, the curing is carried out at a temperature of 45 ° C to 55 ° C for a period of 4 to 72 hours, preferably at least 24 hours.

The The invention further relates to a process for producing a stabilized solid oral sustained-release dosage form containing tramadol contains as active ingredient, comprising preparing a matrix comprising tramadol or a pharmaceutically acceptable salt thereof dispersed in a matrix a hydrophobic material comprising a waxy substance, wherein the wax-like substance during the preparation of the matrix melted or softened and then the matrix at a sufficient Temperature and for cured for a sufficient amount of time is reached, so that an end point is reached at which the matrix provides stable release profile. The endpoint is through Compare the release profile of the matrix immediately after the hardening with the release profile of the matrix after exposure to accelerated Storage conditions of at least one month at 40 ° C and 75 % relative humidity. The matrix can be a variety of pharmaceutically acceptable particles (such as granules) or a tablet include. In preferred embodiments the matrix is pressed into a tablet. The method of manufacture a stabilized solid oral sustained-release dosage form, containing tramadol according to the present invention Invention, may be any process which is a wax or a Wax-like material in the matrix and including the wax or the wax-like material during the preparation of the dosage form is softened or melted. In certain preferred embodiments the formulation is prepared by adding tramadol and hydrophobic Material together with other optional pharmaceutical excipients in an extruder at elevated temperature, which is sufficient to soften the waxy material or to melt; Extruding the mixture; Granulating the mixture; Lubricating ("lubricating") the granules and optional subsequent Pressing the granules into tablets. In further preferred embodiments For example, the formulation is prepared by spraying a hydrophobic polymer dispersion to a mixture of tramadol and an inert diluent in a fluidized bed dryer ("fluid bed dryer ") To obtain granules; Mix the molten waxy substance into the granules with a high shear mixer; Happen mixing through a sieve and mixing with talc; Lubricating ("lubricating") the resulting Material and optionally pressing the lubricated granules into tablets. In further preferred embodiments the invention, the formulation is prepared by pouring the melted wax-like substance on the tramadol in a pharmaceutical suitable mixer; cooling down leave and solidify the mixture and then grinding the mixture; Lubricating ("lubricating") the mixture and Pressing the lubricated granules into tablets. In another Alternative preferred methods are formulations of the invention by melting and granulating a waxy substance; Hydrating a cellulose ether and granulating the same; Mixing tramadol with one the granulated melt, the granulated cellulose ether or a mixture of them; Drying the granules and then optional Mix with a suitable amount of an inert pharmaceutical acceptable diluent and pressing the blend tablets.

In Embodiments, where the hydrophobic material is a hydrophilic or hydrophobic polymer additionally to the waxy substance, the formulation can be prepared are by (a) wet granulating the hydrophobic or hydrophilic Polymers and optional diluents with or without tramadol; (b) drying and classifying (sizing) the resulting granules; (c) combining the tramadol with the granules, if not previously performed in step (a); Include the Wax-like substance in a molten state in the granules using a suitable mixer; (d) cooling and Classifying ("sizing") the granules; and then (e) optionally lubricating the granules and pressing the lubricated granules to tablets.

In Another aspect of the invention is a method of treatment of a patient by administering a solid oral dosage form with delayed Release of tramadol provided which stable release, as described herein.

In preferred embodiments of the invention, the hardening of the solid dosage form containing tramadol gradually slows release of the active ingredient when exposed to ambient fluid so that the cured formulation provides stabilized release of tramadol which is unchanged after exposure to accelerated storage conditions. the stabilized release of the Food and Drug Administration of the United States, the Committee of Proprietary Medicinal Products ("CPMP") is considered appropriate in Europe and other similar government regulators regarding the expiration date of the formulation. For example, curing may be continued for a time sufficient for a curing endpoint to be reached to provide a stabilized release of the dosage form of tramadol, which is unchanged after exposure to the accelerated storage conditions. The endpoint can be determined by comparing the release profile of the formulation immediately after curing with the release profile of the formulation after exposure to accelerated storage conditions, eg, one to three months at a temperature of 37 ° C and 80% relative humidity.

In further preferred embodiments will harden the oral sustained release solid dosage form, according to Exposure to accelerated storage conditions of at least one month 40 ° C / 75 % relative humidity, release an amount of tramadol, which at no given release time by more than about 20 % of the total amount of tramadol used varies with in vitro release obtained prior to storage.

In further embodiments provides the sustained-release oral solid dosage form of tramadol while of in vitro release testing, a range after exposure across from accelerated storage conditions ready, which no longer than about 20% at any time is different compared to the Release profile before exposure to accelerated storage conditions.

The Terms "stable Release profile "and" cure endpoint "are defined for the purpose of the present invention, such that the cured solid dosage form (e.g., a tablet) reproducibly releases the drug (e.g., tramadol) when placed in a use environment is placed, which unchanged even after exposure of the cured formulation to accelerated storage conditions. The person skilled in the art will recognize that by "unchanged" is meant that any change in the release of the active ingredient from the cured formulation as insignificant in relation to the desired Effect is considered. For pharmaceutical formulations, stability, e.g. through a regulatory agency like the Food & Drug Administration (FDA) in the U.S.A. or by the Committee on Proprietary Medicinal Products ("CPMP") in Europe, for the purpose of measuring the expiration date for the formulation.

With the term "accelerated Storage Conditions "is meant, e.g. Storage conditions at elevated temperature and / or elevated relative Humidity. Preferably, the term "accelerated storage condition" refers to storage conditions, the drug formulation for the purpose of obtaining the regulatory Approval (e.g., FDA approval in U.S.A.) and specification expiration date.

Of the Term "expiration date" is defined for Purpose of the present invention, as the date, which is the time indicating while of a batch of the product (e.g. coated substrate) is expected within the specifications to stay when stored under defined conditions, and after which it should not be used anymore.

Of the The term "bandwidth" is for the purpose of this Invention defined as the difference in in vitro release measurements of the formulations with delayed Release, when comparing the release profile (curve), the is obtained by the formulation after the completion of the preparation the coated product (before storage) with the release profile, which is obtained after the coated product has accelerated Storage conditions, expressed as the change in percent of the active ingredient, that of the coated product released at each release time along the release curve becomes.

Of the The term "delayed release" is defined for the purpose of this invention as the release of the active ingredient (i.e., tramadol) at such a rate that blood (e.g., plasma) levels are within of the therapeutic range, but below the toxic level be held over a period greater than 6 hours, more preferred for a period of about 12 hours (i.e., twice a day) or about 24 hours (i.e., once a day) or longer. The term "sustained release" is intended to include the term "prolonged release" as used by the term "sustained release" CPMP is used.

The term "curing" is defined for the purpose of this invention, as the heat treatment of the dosage form (or intermediate) for the purpose of obtaining a finished stabilized oral sustained release pharmaceutical dosage form as defined above. When the formulations of the invention include a polymer as part or all of the hydrophobic retarder, those skilled in the art will understand that a heat treatment causes a hardening effect and that the polymer may possibly cross-link with itself to a more stable state. If the formulations of the invention do not include a polymer but rather a hydrophobic material such as hydrogenated vegetable oil or stearyl alcohol, those skilled in the art will recognize that the heat treatment is more similar to annealing the formulation than curing the polymer. For the purpose of the present invention, the use of the term "curing", both curing and / or annealing will be included.

SHORT DESCRIPTION THE DRAWINGS

The The following drawings illustrate embodiments of the invention and are intended to cover the scope of the invention as encompassed by the claims will not limit.

1 Figure 4 is a graph of mean tramadol plasma concentration (ng / ml) over 24 hours on the fifth day after multiple doses of Example 7 and Ultram ^™ .

DETAILED DESCRIPTION

tramadol, which is the chemical name (±) -trans-2 - [(dimethylamino) methyl] -1- (3-methoxyphenyl) cyclohexanol wearing, is an orally active opioid analgesic. Preparations with conventional Release in the form of capsules, drops and suppositories, containing tramadol, or more preferably its hydrochloride salt, have been for several years for its use in the treatment of moderate to severe pain commercially available. Such preparations but do not get delayed Release of tramadol. Despite the long-term use of tramadol are so far no preparations with delayed Release for the oral administration containing tramadol as an active ingredient in the Literature has been described.

suitable pharmaceutically acceptable salts of tramadol for use in accordance with the present invention Invention are those that are conventional as pharmaceutically acceptable acid addition salts are known in the art. The hydrochloride salt is special prefers.

According to the present Invention is delayed Release of the active ingredient, the therapeutic agent homogeneous with a sufficient amount of a hydrophobic (release delaying) Material mixed, which is a wax or a wax-like material includes. The hydrophobic material may also be hydrophobic Polymer, e.g. a water-insoluble Acrylic acid polymer or alkyl cellulose.

It is surprising found that when using a matrix formulation of tramadol with delayed Release is made, in which the wax or wax-like Material is incorporated by a method in which it softens or is melted, the final one Matrix formulation with delayed Release (e.g., a tablet) no stable release profile after exposure to accelerated storage conditions, as this term defines here is, has. It is believed that tramadol itself is physical Has properties which make such formulations "softer". With others Words, it is believed that tramadol itself is a softening Has effect on such matrix formulations, which one softened or include melted wax or waxy material and that these physical properties of tramadol to the defect in stability contributes to such products. It should be noted that these hypotheses are presented for explanatory purposes only become; The inventors do not want to be limited by these hypotheses be and the attached claims should by no means be interpreted in such a way.

by virtue of However, the present invention can be a matrix formulation with delayed Release containing tramadol in a matrix containing a wax or a wax-like material, are made in one Way that gives the formulations stability (as stability is defined here).

In In particular, the final product, such as e.g. a tablet, cured to an endpoint at which the tablet has a reproducible, stable release profile, even after facing the suspension accelerated storage conditions or after extended Store at room temperature.

It can pharmaceutical dosage forms are developed in which the Release rate of the drug (s) somehow modified are compared to conventional ones Formulations. Such change In the release of the active substance can be a set of goals but the intention of this statement is to make such formulations cover in which the release of the active substance somehow extended is used to reduce the therapeutic activity for the reduction of toxic To obtain effects or other therapeutic purposes.

As in the "Notes for Guidance on Prolonged Release Oral Dosage Forms ", Form 3A115A (January 1996) by the European Committee on Proprietary Medicinal Products ("CPMP") the details included in the application for the approval needed will generally include: the therapeutic purpose; the Nature of the active substance; the nature of the formulation, the way the administration and it must data is provided in many sections of the dossier, to support the registration, which take into account these numerous requirements. areas which must be taken into account in the application for marketing authorization, conclude in vitro tests of oral solid dosage forms in which the release of the active ingredient the rate-limiting step in the absorption forms.

The mentioned above CPMP guideline shows that the release rate through a release test procedure should be tested in vitro, which has shown that between Distinguished batches with acceptable and unacceptable in vivo performance can be. Test conditions that are the most appropriate demarcation Show should be chosen become. The release devices should preferably be those by the authority, who checks the application, are accepted. For example, in Europe, the release apparatus preferably described in U.S. Pat. or European Pharmacopoia. In In such tests, the test medium should preferably be water-based be; organic or aqueous-organic Media should preferably be avoided. For poorly soluble substances can a minimum level of a suitable surfactant. Buffer solutions at a pH above reach the physiological range (pH 0.8-2, stomach, pH 5-6.5 jejunum ( "Jejunum"); pH 6-7.5, ileum; Davis et al. 1989) used to increase the relationship between release and pH determine. The data obtained could be obtained using three-dimensional release profiles (i.e.,% released as a Function of time and pH) are displayed suitably.

Around an adequate one To achieve distinction, the CPMP guidelines show that it may be necessary, the solubility of the medical product (therapeutic agent) and yet to achieve sink conditions in the release medium. It may also be necessary to increase the ionic strength and surface tension to look at the medium. The volume of the medium used should be prefers storage conditions ("sink conditions "), which can be accepted when the amount of substance in solution does not exceed 30% of the saturation concentration. The solubility the substance in the chosen one Release medium should be indicated. Identical test conditions should for different strengths of the same product. The robustness of the release test should by studying the effect of the release rate at changes be determined by temperature, pH and rotational speed.

The definitive release profile and the corresponding specification (for the Marketing Authorization) is preferred for in vitro results of batches supported which are based on in vivo tests and preferably provides a hedge prepared that the batches routinely show the desired in vivo behavior.

• a) Vergleich der in-vitro-Freisetzungskurven des Produktes mit den in-vivo-Freisetzungskurven, erzeugt durch Dekonvolution der Plasmagehaltsdaten oder durch andere geeignete Verfahren;
• b) Vergleich der mittleren in-vitro-Freisetzungszeit des Produktes mit entweder der mittleren in-vivo-Verweilzeit oder der mittleren in-vivo-Freisetzungszeit des Produktes, erhalten unter Verwendung der Prinzipien der statistischen Zeitpunktanalyse ("statistical moment analysis");
• c) Vergleich von mittleren in-vitro-Freisetzungszeit mit einem mittleren pharmakokinetischen Parameter, z.B. den Zeitpunkt bis zur maximalen Plasmakonzentration ("Tmax").

To justify the specification limits in the in vitro release assay, the CPMP guidelines require that an attempt be made to establish a meaningful correlation between in vitro release properties and in vivo bioavailability parameters. To achieve this, a number of techniques can be used. These include in the series with decreasing predictive power:

• a) comparison of the in vitro release curves of the product with the in vivo release curves generated by deconvolution of the plasma content data or by other suitable methods;
• b) comparing the mean in vitro release time of the product with either the mean in vivo residence time or the mean in vivo release time of the product, obtained using the principles of statistical moment analysis;
• c) Comparison of mean in vitro release time with a mean pharmacokinetic parameter, eg the time to maximum plasma concentration ("Tmax").

Other approaches are considered acceptable, especially if the above methods show no correlation. Examples of other approaches include demonstrating the bioequivalence of the pre For example, the formulation limits may be obtained from the range of in vitro release results of batches used in bioavailability assays. The approval authorities generally wish that the choice of approach be justified by the notifier of the marketing authorization.

The final Product specification in the application for marketing authorization generally includes one Release test. The release specification is not only important for Ensuring a consistent release of substance from batch to batch at the time of manufacture, but also to acceptance limits for the Release of the product during its durability. The release specifications should from the profile / profiles during the development of the product were derived and with pilot batches of production quantities be revalidated. The selection of specifications should include pharmacokinetics, Consider pharmacodynamics and in vitro assay precision. In general (and in particular with regard to the aforementioned CPMP Directive) a minimum of three points should be included: an early point in time, to rule out can dumping, at least one point to the match ensure the form of the release profile and one to ensure that the majority of the substance was released. Where both, the lower and upper limits are specified at each time point, The difference between these should not normally be 20% of the exceed the stated amount of active substance in the formulation, if not shown in other limits, they are a reproducible one and achieve acceptable in vivo behavior.

Requirements the relevant authorities, e.g. U.S. Pat. FDA or the CPMP require the demonstration that the release profile of the active substance during the proposed shelf life of the product within the specification.

Where the release specifications correlated with in vivo results were, can minor changes be acceptable on the basis of in vitro tests. Minor changes close changes in the Composition (e.g., the nature and / or quantity of excipients which not affecting the release characteristics), method or Place of manufacture or manufacturing equipment. Bigger changes however, require further in vitro / in vivo correlation studies or in-vivo bioavailability studies.

hydrophobic material

The hydrophobic material comprises a wax or a waxy material (hereinafter referred to as "waxy substance"). The hydrophobic material used in the formulations of the present invention is a material such as a natural or a synthetic wax or oil, for example hydrogenated fats such as hydrogenated vegetable oil, hydrogenated castor oil, microcrystalline wax, normal waxes, beeswax, carnauba wax , Paraffin or glyceryl monostearate and suitably has a melting point of 35 to 140 ° C, preferably 45 to 110 ° C. Hydrogenated vegetable oil is particularly preferred. Alternatively, or in addition to the above materials, the wax or waxy substance used in the formulations of the present invention may include fatty alcohols, fatty acid esters, fatty acid glycerides (mono-, di- and tri-glycerides), higher aliphatic (eg C ₁₀ -C ₂₀ ) acids, alcohols, long chain fatty acids and mixtures thereof. Suitable water-insoluble waxy substances may be those having a water solubility less than about 1: 5,000 (w / w).

Of the Aliphatic alcohol may suitably be lauryl alcohol, myristyl alcohol or stearyl alcohol, but is preferably cetyl alcohol or more preferably cetostearyl alcohol.

In addition to The waxy substance includes certain preferred embodiments another hydrophobic polymer as part of the hydrophobic material one.

A particularly suitable sustained-release matrix includes a hydrophobic polymer comprising one or more alkylcelluloses and one or more C ₁₂ -C ₃₆ aliphatic alcohols. The alkylcellulose is preferably a C ₁ -C ₆ alkylcellulose, especially ethylcellulose.

In further embodiments of the present invention, the hydrophobic polymer is a pharmaceutically acceptable acrylic acid polymer including, but not limited to, acrylic acid and methacrylic acid copolymers, methyl methacrylate copolymers, ethoxyethyl methacrylates, cyanoethyl methacrylates, aminoalkyl methacrylate copolymer, poly (acrylic acid), poly (methacrylic acid) , Methacrylic acid alkylamide copolymer, poly (methyl methacrylate), poly (methacrylic acid) (anhydride), methyl methacrylate, polymethacrylate, poly (methylme thacrylate), poly (methyl methacrylate) copolymer, polyacrylamide, aminoalkyl methacrylate copolymer, poly (methacrylic anhydride) and glycidyl methacrylate copolymers.

In particularly preferred embodiments, the acrylic acid polymer comprises one or more amminomethacrylate copolymers. Amminomethacrylate copolymers are well known in the art and described in NF XVII as fully polymerized copolymers of acrylic and methacrylic acid esters with a low content of quaternary ammonium groups. Such an acrylic acid polymer is an acrylic resin lacquer commercially available from Rohm Pharma under the trade name Eudragit ^®.

Further hydrophobic polymers used in the formulations of the present invention Include cellulose polymers including others Alkylcellulose polymers such as e.g. Ethylcellulose.

The Release of the active ingredient of the sustained-release formulation The present invention may be further influenced, i. adapted to a desired Rate, by the addition of one or more release-modifying Means in the matrix. The release modifying agents may include or more water-soluble Hydrophilic polymers include the release characteristics of the formulations. example for suitable hydrophilic polymers include hydroxypropyl methylcellulose, Cellulose ethers, acrylic resins and materials derived from proteins. Of these Polymers are cellulose ethers, in particular hydroxyalkylcelluloses and carboxyalkyl celluloses, preferred. It can also be synthetic Water-soluble Polymers such as e.g. Polyvinylpyrrolidone, cross-linked polyvinylpyrrolidone, Polyethylene oxide, etc. and polysaccharides such as e.g. Pullulan, dextran, Sucrose, glucose, fructose, mannitol, lactose, mannose, galactose, Sorbitol and mixtures thereof are used. In certain preferred embodiments In the present invention, the hydrophilic polymer comprises hydroxypropyl methylcellulose.

semipermeable Polymers can also be incorporated into the matrix to determine the release characteristics to change the wording. Such semipermeable polymers include, for example, cellulose acylates, Acetates and other semipermeable polymers such as those described in U.S. Patent No. 4,285,987, as well as optionally permeable polymers, formed by the co-precipitation a polycation and a polyanion as disclosed in U.S. Patents No. 3,173,876; 3,276,586; 3,541,005; 3,541,006 and 3,546,142.

The hydrophobic polymer usually comprises a plasticizer. Examples for suitable Plasticizer for Close ethylcellulose Water-insoluble Plasticizers such as e.g. Dibutyl citrate, dibutyl sebacate, diethyl phthalate, Triethyl citrate, tributyl citrate and triacetin, although it is possible that more water-insoluble Plasticizers (such as acetylated monoglycerides, phthalate esters, Castor oil, etc.) can be used. examples for suitable plasticizers for Acrylic acid polymers The present invention includes citric acid esters such as. Triethyl citrate NF XVI, tributyl citrate, dibuyl phthalate and possibly 1,2-propylene glycol, polyethylene glycols, propylene glycol, diethyl phthalate, Castor oil and triacetin, although it is possible that more water-insoluble Plasticizers (such as acetylated monoglycerides, phthalate esters, Castor oil, etc.) can be used.

Surprisingly can embodiments however, without the presence of plasticizers getting produced. Such embodiments are normally by melt extrusion processes, as herein described, manufactured and are in view of the state of the art Technology unexpected.

In addition to the foregoing, the sustained-release formulations of the invention may include pharmaceutically acceptable carriers and excipients. It is understood that, for example, these materials may also be mixed with particles after extrusion. Specific examples of pharmaceutically acceptable carriers and excipients that can be used to formulate oral dosage forms are described in the Handbook of Pharmaceutical Excipients, American Pharmaceutical Association (1986). Techniques and compositions for the preparation of solid oral dosage forms are described in Pharmaceutical Dosage Forms: Tablets (Lieberman, Lachman and Schwartz, Editors) Second Edition, published by Marcel Dekker, Inc. Techniques and Compositions for Making Tablets (Pressed and Melted) , Capsules (hard and soft gelatin) and pills are also described in Remington's Pharmaceutical Sciences, (Arthur Osol, Editor), 1553-1593 (1980). Pharmaceutically acceptable ingredients which are often in the pharmaceutical art include diluents, lubricants, binders, granulating aids, colorants, flavorants, Ten side, pH adjusters, anti-adherents and glidants, eg dibutyl sebacate, ammonium hydroxide, oleic acid and colloidal silica.

The preparations with delayed Release according to the invention can e.g. as granules, multiparticulates, capsules or tablets. Tablets are preferred. The sustained release formulations according to the invention can be suitably film-coated using any Film coating material used in the pharmaceutical art suitable is. Preferably, an aqueous film coating is used.

In certain embodiments According to the invention, the granules or tablets are film-coated. The Granules can and then either in dosage units of tramadol (e.g., and placed in a gelatin capsule) or pressed into tablets become. In the same way Tablets made according to the invention be produced, be film-coated. The film coating can be before or after the curing step carried out become. In general, the film coating essentially comprises a hydrophilic polymer such as e.g. Hydroxypropylmethylcellulose and does not affect the release rate of the active ingredient of the formulation. The film coatings that can be preferably used are able to produce a strong, continuous film, the smooth and elegant, suitable for pigments and other coating additives to support, non-toxic, inert and non-tacky ("tack-free").

In certain further embodiments of the invention, the film coating may contribute to the release properties of the dosage form. In such cases, the dosage form, eg, granules or tablets, may be coated with a sufficient amount of hydrophobic material to achieve a weight gain content of from about 1 to about 30 percent. The solvent used for the hydrophobic material may be any pharmaceutically acceptable solvent, including water, methanol, ethanol, methylene chloride, and mixtures thereof. However, it is preferred that the coatings be based on aqueous dispersions of the hydrophobic material. However, the hydrophobic polymer used in such film coatings can, for example, comprise a pharmaceutically acceptable acrylic polymer, including but not limited to acrylic acid and methacrylic acid copolymers, or an alkylcellulose such as ethylcellulose, such as a commercially available aqueous dispersion of ethylcellulose known as Aquacoat ^® (FMC Corp. Philadelphia, Pennsylvania, USA). The acrylic acid polymer is in certain cases, preferably one or more Amminomethacrylat copolymers, commercially available from Rohm Pharma under the trade name Eudragit ^®. In order to prepare tablets according to the invention, particles prepared according to the invention may be mixed or blended with the desired excipients / adjuvants, if provided, using conventional methods, for example using a Y-cone or mixer "Blender") and the resulting mixture is pressed according to conventional tabletting procedures using tablet forms of suitable size. Tablets can be made using conventional tabletting machines and in the embodiments described below they are made on a standard single punch machine (F3 Manesty machine) or a Kilian RLE15 rotary tableting machine. The tablets of the present invention may have any suitable shape such as round, oval, biconcave, hemispheric or any polygonal shape such as a square, rectangle, and pentagonal or the like.

Of the Active ingredient (tramadol) in the formulations according to the present invention is incorporated into the controlled release matrix. The Matrix preferably allows sustained release of the tramadol over at least a twelve Hour period and prefers that the in vitro release rates and in vivo absorption rates of the tramadol within those specified herein Areas allows becomes. The total amount of tramadol or pharmaceutically acceptable Salt thereof in the matrix of the invention can be used within large limits vary, for example from about 20 to about 80%, preferably from from about 40 to about 60%, and most preferably from about 45 to about 55% by weight. The total amount of hydrophobic material in The matrix of the invention may be from about 80 to about 20%, by weight be. The total part of the hydrophobic polymer (not a waxy Substance as defined herein) as a component of the hydrophobic Material can range from about 0 to about 80%, in certain preferred embodiments from about 20 to about 60%, and most preferably from about 30 to be about 50% by weight. The total amount of additional optional pharmaceutically acceptable ingredients, including inert ones Diluents, Lubricant, etc. may be from about 0 (preferably 0.5%) to about 10 % of the total weight of the formulation.

In a particularly preferred embodiment, the sustained release matrix includes a hydrophobic polymer (eg, ethyl cellulose) and a higher aliphatic alcohol (eg, cetostearyl alcohol). with or without an optional plasticizer.

Around a delayed one Release of tramadol for at least one twelve Hours after oral administration the in vitro release rate prefers the following% rates of released tramadols: released from about 1 to about 50% tramadol after 1 hour; from about 0 to about 75% tramadol released after about 2 hours; from about 3 to about 95% tramadol released after about 4 hours; from about 10 to about 100% tramadol released after about 8 hours; released from about 20 to about 100% tramadol after about 12 hours; released from about 30 to about 100% tramadol after about 16 hours; released from about 50 to about 100% tramadol after about 24 hours; and more than 80% tramadol released after about 36 hours.

One another preferred preparation, especially for one twice a day Dosage is appropriate, has an in vitro release rate accordingly the following percentages (%) of released tramadol: from about 20 to about 50% tramadol released after about 1 hour; from about 40 to about 75% tramadol released after about 2 hours; from about 60 to about 95% tramadol released after about 4 hours; from about 80 to about 100% tramadol released after about 8 hours and from about 90 to about 100% tramadol released after about 12 hours.

A another preferred, particularly suitable embodiment for a once daily Dosage has an in vitro release rate corresponding to following percentages of released tramadol: from about 0 to about 50% tramadol released after about 1 hour; from about 0 to about 75% tramadol released after about 2 hours; from about 10 about 95% tramadol released after about 4 hours; from about 35 about 100% tramadol released after about 8 hours; about 55 to about 100% tramadol released after about 12 hours; from about 70 to about 100% tramadol released after about 16 hours; and more than about 90% tramadol released after about 24 hours.

One further preferred preparation according to the invention, which is also suitable for once a day Dosage, has an in vitro release rate according to the following % Rates of released tramadol: from about 0 to about 30% tramadol released after about 1 hour; from about 0 to about 40% tramadol released after about 2 hours; from about 3 to about 55% tramadol released after about 4 hours; from about 10 to about 65% tramadol released after about 8 hours; from about 20 to about 75% tramadol released after about 12 hours; from about 30 to about 88% tramadol released after about 16 hours; from about 50 to about 100% tramadol released after about 24 hours and more than about 80% tramadol released after about 36 hours.

More Preferably, a preparation for one once a day Dosage has an in vitro release rate that is substantially as follows: from about 15 to about 25% tramadol released after about 1 hour; from about 25 to about 35% tramadol is released after about 2 hours; from about 30 to about 45% tramadol released after about 4 hours; from about 40 to about 60% tramadol is released after about 8 hours; from about 55 to about 70% tramadol released after about 12 hours and about 60 to about 75% tramadol released after about 16 hours.

A further preferred in vitro release rate during the release of the preparation with delayed Release twice a day Administration according to the invention is between about 5 and about 50% (by weight) of tramadol released after about 1 hour, between about 10 and about 75% (by weight) Tramadol liberated after about 2 hours, between about 20 and about 95% (by weight) tramadol released after about 4 hours, between about 40 and about 100% (by weight) tramadol released after about 8 hours, more than about 50% (by weight) of released tramadol after about 12 hours, more than about 70% (by weight) released Tramadol after about 18 hours and more than about 80% (by weight) released tramadol after about 24 hours.

Farther it is preferred in the case of the sustained-release preparation for twice daily administration, that about 8 hours after oral administration between about 70 and about 95% (by weight) of tramadol is absorbed in vivo, between about 77 and about 97% (by weight) of tramadol after about 10 Hours is absorbed and between about 80 and about 100% (after Weight) tramadol is absorbed after about 12 hours.

A formulation according to the invention suitable for twice daily dosing may have a T _{max of} from about 1.5 to about 8 hours, preferably from about 2 to about 7 hours, and a W ₅₀ in the range of about 7 to about 16 Have hours.

A formulation according to the invention suitable for once daily dosing may have a T _max in the range from about 3 to about 6 hours, preferably from about 4 to about 5 hours, and a W ₅₀ in the range of about 10 to about 33 hours.

The W ₅₀ parameter defines the width of the plasma profile at 50% C _max , ie, the duration over which the plasma concentration is equal to or greater than 50% of the peak concentration. The parameter is defined by linear interpolation of the observed data and represents the time difference between the first (or only) cutting up the curve and the last (or only) cutting down the curve in the plasma profile.

The in vitro release rates mentioned herein, if not otherwise indicated by measurements using the USP Apparatus 2 (paddle method) at 100 rpm in pH 6.5 phosphate buffer at 37 ° C. The in vivo absorption rates can by measuring the plasma concentration against time using be determined by Dekonvolutionstechniken or by HPLC method.

The Delayed formulations Release according to the invention preferably contain an analgesically effective amount of tramadol or a pharmaceutically acceptable salt thereof, usually in the range of about 50 to about 800 mg, especially 100, 200, 300, 400 or 600 mg (calculated as tramadol hydrochloride) per unit dose.

The Delayed formulations Release of the present invention set the therapeutic Drug slowly released, e.g. when taken and the gastric fluid and subsequently the intestinal fluids exposed. That delayed Release profile of the formulation of the invention can be altered for example, by varying the amounts of delaying agent, i. hydrophobic Polymer, by varying the amount of plasticizer relative to hydrophobic Polymer, by the inclusion of additional ingredients or Auxiliaries, through change of the manufacturing process, etc.

manufacturing the dosage forms

The Formulations of the invention may through any of the multitude of methods known to those skilled in the art Technique of pharmaceutical formulations are known in which are the hydrophobic material incorporated into the matrix is softened, or at least softened.

One particularly preferred method for the preparation of the dosage form of the present invention (both multiparticulates and tablets) includes a: direct dosing of a water-insoluble retarding agent, a therapeutic agent and an optional binding agent in an extruder; Heating the homogeneous mixture; Extrude the homogeneous mixture, thereby forming strands; Cooling the strands, the containing the homogeneous mixture and cutting the strands into particles, the size of about 0.1 mm to about 12 mm and dividing the particles in dosage units. In this aspect of the invention becomes a relatively continuous Realized manufacturing process.

In a preferred embodiment An oral dosage form is made to be effective To include amount of multparticles by granulation of the extrudate and then the lubricated granules pressed into tablets. alternative can be a variety of molten, extruded particles in a gelatin capsule are placed.

A typical melt extrusion system capable of carrying out the present invention includes a suitable extruder drive motor having variable speed and constant torque control, start-stop control, and an ammeter. Additionally, the system should include a temperature control console that includes temperature sensors, coolants, and temperature indicators along the length of the extruder. In addition, the system will include an extruder, such as a twin-screw extruder, which consists of two intermeshing screws enclosed in a cylinder or drum having an opening or nozzle ("the ") at the output. The feed materials enter through a feed chute and are moved through the drum by means of the screws and pressed through the nozzle ("die") into strands, which are then conveyed, for example, through a continuous movable belt to cool and to a pelletizer or other suitable device to bring the extruded strands ("ropes") in the multiparticulate system. The pelletizer may consist of rollers, fixed blades, rotating blades and the like. Suitable instruments and systems are available from distributors such as CW. Brabender Instruments, Inc. of South Hackensack, New Jersey. Other suitable devices are the Professional obviously.

One general pellet production process, which according to the invention can be applied is as follows: Premix the required amount on active ingredient, polymers and optional binders (wax). Loaded a powder feeder ("powder Feeder ") with a suitable amount of active ingredient / excipient mixture. Setting the temperatures of the extruder to the needed Temperature in dependence the formulation. Wait until the corresponding heating zones have a stable temperature achieved. Starting the feeder and the extruder. The active ingredient / excipient powder mixture is melted and thoroughly mixed in the extruder. The diameter the extruder opening can be adjusted to the thickness of the resulting strand too vary. Adjusting the conveyor belt speed to a suitable speed (e.g., 3-100 feet / min). Solidification of the extruded semi-solid strand / strands and transport to the pelletizer. Additional cooling devices may be needed for proper cooling sure. (The conveyor belt does not have to be cooled if the material solidifies fast enough.). Setting the Roller speed and blade speed (e.g., 3-100 feet / min 100-800 rpm). Cutting the solidified strands into desired sizes (e.g., 3-5 mm in diameter, 0.3-5 mm in the length). Collecting the pellet product. bottling of the desired Weight of the pellets in hard gelatin capsules to a suitable Dose of the active ingredient.

One another method for the preparation of a formulation according to the invention comprises (a) mechanically processing a mixture of tramadol or a pharmaceutically acceptable salt in particulate form in a high speed mixer and a particulate, hydrophobic fusible carrier material or diluents, which has a melting point of 35 to 140 ° C and optionally a Release control component that is a water-soluble fusible material or a particulate, soluble or insoluble, organic or inorganic material comprises at a rate and an energy input which is to the carrier or diluent allowed to melt or soften, forming agglomerates become; (b) breaking up the larger agglomerates, to achieve controlled release germs and (c) continue the mechanical processing with optionally a further supply of low percentages of the carrier or diluent. Steps (c) and possibly (b) can be repeated one or more times. Stage (a) of the process can in conventional High-speed mixers with an interior of standard stainless Steel, e.g. a Collette Vactron 75 or equivalent mixer. The mixture is processed until a bed temperature of about 40 ° C or above is reached and the resulting mixture is a cohesive granular texture ("cohesive granular texture ") has, reaching with particle sizes from about 1-3 mm to fine powder in the case of non-aggregated starting material. Such a material has in the case of the embodiments described below be the appearance of agglomerates, which during the cooling below 40 ° C a structural integrity have and "resistance" over the Crush between has the fingers. At this stage, the agglomerates are of irregular size, shape and appearance. The agglomerates are preferably cooled. The Temperature to which cooled is not critical and has a temperature in the range of Room temperature up to 37 ° C can usually be applied. The agglomerates are replaced by any suitable Broken down, which will reduce oversized agglomerates and one Mixture of a powder and small particles, preferably with a Diameter below 2 mm will produce. It is currently preferred the classification using a Jackson Crockatt granulator using a sieve of suitable size or a comil with a Sieve of suitable size. As said to be too small mesh sizes used in the aforementioned devices become agglomerates under the movement of the bat or wing ("impeller") clog the sieve and prevent further passage of the mixture, which reduces the yield. A sieve size of 12 was considered suitable. The classified material becomes returned to the high-speed mixer and processing continued. It is believed that this will lead to cementation ("cementation") of the finer particles into particles of a uniform size range.

In A preferred form of the method of the invention is the classified Material is further processed until the hydrophobic fusible material, which is used to soften / melt starts, and optional then additional hydrophobic fusible material is added. The mixing is continued until the mixture into particles of the desired, predetermined size range is transformed.

In certain processes it is preferred to supply at least a portion of the energy input into the constituents in the high speed mixer by means of microwave energy to ensure uniform energy. Energy may also be supplied by other means such as a heating mantle or by the mixing blade or chopper blades. After the particles ge are cooled, or allowed to cool, and are then screened to remove any oversized or undersize material.

The resulting particles can used to dosage units in accordance with the invention in the form of e.g. Tablets or capsules in a conventional manner manufacture.

The Formulations of the invention may also be prepared according to the procedure, as set forth in U.S. Patent No. 3,965,256 (Leslie), which teaches slow release pharmaceutical composition is directed, which is a combination one higher aliphatic alcohol and a hydrogenated hydroxyalkyl cellulose includes. These formulations can e.g. by melting and granulating the higher aliphatic alcohol; Hydrating the hydroxyalkyl cellulose and granulating the hydrated one Cellulose compound; Mix the active ingredients with either granulated melt, granulated alkyl cellulose or a mixture thereof and drying the mixture of the granules become. After that, the granules are optional with an appropriate amount a pharmaceutically acceptable diluent and pressed into tablets.

The Formulations of the invention may also in agreement with the procedures described in U.S. Patent Nos. 4,861,598 and 4,970,075 (Oshlack et al.), Wherein the release of the therapeutic Active ingredient of delayed Release basis by using a combination of a higher aliphatic Alcohol and an acrylic resin extended as base material becomes. The dosage form is e.g. through a wet granulation process produced, with most of the excipients (including optional pharmaceutically acceptable diluent, if tablets are to be produced as the ultimate product) with or without the therapeutic agent together with a granulation fluid combined until a moist granulation mass obtained becomes; the mass is dried and the resulting granules are sized ( "Sized"); the higher aliphatic Alcohol is melted and used in the warm granules a suitable mixer introduced. After cooling, be the granules are sized. Optional then the granules lubricated and pressed into tablets.

stabilization the formulations

Around the hardening To achieve the invention, the final formulation will prolong elevated temperatures exposed to stability to achieve. In situations where the hydrophobic material only includes a waxy substance, curing is preferred at a temperature of about 35 ° C up to about 65 ° C carried out, for one Time sufficient to reach stability. In particular preferred embodiments of the invention, the hardening at a temperature of about 35 ° C up to about 65 ° C for one Period of about 4 to about 72 hours. In certain preferred Embodiments will the hardening at a temperature of about 40 ° C up to about 60 ° C for one Period of about 5 to about 24 hours. In certain preferred embodiments is the raised one Temperature about 50 ° C. It should be mentioned be that period that for the hardening needed to an endpoint becomes, as described above, actually longer or shorter can be as the period mentioned above. Such curing times, which the desired Result of a stabilized formulation are called through the attached claims includes considered.

In certain preferred embodiments will harden at a temperature of about 45 ° C to about 55 ° C for one Period of about 4 to about 72 hours, preferably at least about 24 hours.

The Glass transition temperature (Tg) is related to the temperature or the temperature range, in which there is a fundamental change in the physical properties of the polymer. This change does not change the condition, but rather a change in the macromolecular mobility of the polymer. Below Tg, the mobility of the polymer chain is severely limited. Therefore will, for one given polymer, if its Tg is above room temperature, the polymer behave like a glass, hard, not flexible and rather brittle properties that can be somehow restrictive for film coatings since the coated dosage form of a certain amount of external May be subjected to stress. In addition, the person skilled in the art will recognize that it is possible is, the formulation of the present invention in a different kind and way to harden, to reach the end point where the coated substrate achieved a stable release profile. Such additional hardening, which the desired Result of a stabilized formulation will also be as by the attached claims includes viewed.

Of the curing endpoint can be determined by comparing the release profile of the cured final formulation immediately after curing (herein referred to as "the initial Release profile ") to the release profile of the formulation after exposure to the accelerated storage condition or prolonged storage at room temperature be determined. In general, the cure endpoint will be through the comparison of the release profile of the formulation after exposure to accelerated Storage conditions of e.g. 37 ° C / 80 % relative humidity or 40 ° C / 75 % relative humidity for a period of one month to the initial release profile certainly. The cure endpoint however, further by continuing the exposure of the cured, coated formulation opposite accelerated storage conditions for a further period and Compare the release profile of the formulation after the other Exposure of e.g. two months and / or three months from that initial Release profile, which was obtained to be confirmed.

In certain preferred embodiments becomes the cure endpoint obtained when the data points against a graph of the release curve applied after e.g. accelerated towards exposure Storage conditions for 1-3 months have received a release of the active substance (tramadol) show which at any given time by more than about 20 % of the total amount of the active ingredient varies, which is released compared to in vitro release, which was performed before storage. Such a difference in the in vitro release curves, which in the technique is referred to as a "band range" or a "band width", is of e.g. 20%. In general, when the in vitro release before storage and after exposure to accelerated storage conditions not more than e.g. about 20% of the total amount of the active substance, which is released varies, the formulation is considered acceptable considered when viewed by government regulators e.g. U.S. Pat. FDA for stability considerations and expiration date. Be acceptable bandwidths determined by the FDA on a case-by-case basis and any bandwidth for a certain pharmaceutical, which is regulated by the state regulators as would be considered acceptable would as under the attached claims be considered falling. In preferred embodiments, the above called bandwidth not more than 15% of the total amount of the released Be effective drug. In more preferred embodiments, the bandwidth is not more than 10% of the total amount of active substance released.

in the general are the length of the studies and the storage test conditions imposed by the regulatory authorities the FDA for pharmaceutical formulations are required, sufficient to Cover storage, shipping and subsequent use. Permissible storage test conditions can dependent on vary from the specifics of the product. For example, should temperature sensitive drug substances at alternative low temperature conditions are stored, which then as long-term storage temperature is seen. In these cases, It is generally accepted that the accelerated tests at a Temperature of at least 15 ° C be performed above this designated long-term storage temperature should, along with appropriate relative humidity condition for this temperature.

One generally accepted accelerated test, which in the FDA guidelines is used, relates to the storage of a drug product (e.g., in its container and packaging) at 80% Relative Humidity (RH) and 37 ° C (1985 FDA Policies). If the product is for e.g. three months under these Conditions holds (chemical stability, Release and physical properties), then the drug product e.g. a two year old Shelf life assigned. This accelerated test will now also considered acceptable when exposed to 75% relative humidity and 40 ° C (FDA 1987 guidelines) becomes. It is recent have been proposed that long-term storage tests for pharmaceutical formulations at 25 ° C ± 2 ° C and not more than 60% relative humidity ± 5% for a minimum period of 12 months become. It has also been suggested that accelerated tests for pharmaceutical Formulations at 40 ° C ± 2 ° C at 75 % relative humidity ± 5% for one Minimum period of 6 months. All the above accelerated test criteria and others are considered equivalent for the Purpose of the present invention with respect to the determination of stability and the determination of the cure endpoint accepted.

DETAILED DESCRIPTION THE PREFERRED EMBODIMENTS

The The following examples illustrate numerous aspects of the present invention Invention. They are in no way to be considered as limiting the claims.

example 1

The formulation of Example 1 was prepared by a melt extrusion / granulation technique as follows:
The drug and all of the excipients were mixed in a suitable mixer and the mixture was placed in a powder feeder. The mixture was then fed to a twin-screw extruder at elevated temperatures. The twin-screw extruder consisted of a pair of counter-rotating. Screws and a drum block, equipped with heating / cooling zones. The extrudate came out as a thick strand and was solidified on a conveyor belt and broken into smaller pieces.

After this the excipients were melted and the active ingredient in the molten Embedded mixture, the viscous mass was extruded. The Extrudate was solidified and solidified while on the conveyor belt continued has been. The extrudate was then fitted with a FitzMill with a # 1521-0065 sieve, granulated. The resulting granules was then mixed with talc and lubricated with magnesium stearate. The lubricated granules were pressed into tablets.

The Ingredients of Example 1 are listed in Table 1 below:

Table 1

The Tablets of Example 1 were prepared by the following in vitro release procedures tested. The release tests were carried out with a USP apparatus II (paddle method) at 100 rpm in pH 6.5 phosphate buffer at 37 ° C. The in vivo release rate Tramadol HCl of Example 1 tramadol tablets was carried through an HPLC method is determined. (This release process was used in all examples). The tramadol tablets of the example 1 provided an in vitro release which showed that the product for one once a day Administration is suitable.

The Release results are listed in Table 2 below:

Table 2

• FC = filmbeschichtet; 2 W = 2 Wochen Lagerungszeit (nach der Filmbeschichtung)

The tablets of Example 1 were then film coated with Opadry ^® Beige (Y-1-17181-A from Coloron, Inc.) to a weight gain of 4%. Opadry YS-1-17181-A Beige includes hydroxypropyl methylcellulose, titanium dioxide, polyethylene glycol 400, synthetic yellow iron oxide, synthetic red egg senoxid and polysorbate 80. The inlet temperature of the coating process was set at about 50 ° C with an outlet temperature of about 40 ° C. The spray rate used was about 6-10 g / min. with an air volume of about 60 cfm. The tablets were then stored at 40 ° C and 75% relative humidity for two weeks. The following release results indicate that the drug release rates that followed the coating and storage were progressively slower. Since the coating material used was a high water-soluble polymer and the coating content was low (4%), it was surprisingly found that the drug release rate was lowered at relatively high temperatures used in the coating process (40 ° C outlet temperature) and subsequent storage were. This was demonstrated by the in vitro release results set forth in Table 3 below, which gave the release data obtained from Example 1 initially after product preparation (including film coating) and then the release data obtained from Example 1 after two Weeks storage under ambient conditions (ie room temperature, ambient humidity): Table 3

• FC = film-coated; 2 W = 2 weeks storage time (after film coating)

Example 2

The Tablets of Example 2 were made using the same manufacturing method prepared as Example 1. The two batch lots of the tablets (Examples 1 and 2) showed similar Drug release rates at time zero (release was immediately after production in accordance carried out by the methods as shown in Example 1). To One month storage under ambient conditions showed the tablets a lower release rate (release carried out in similar Manner as in Example 1). The uncoated tablets were then in a 50 ° C oven for 1 hour placed. The following results show that the release rate the tablet after hardening at 50 ° C for 1 hour clearly was slower.

Table 4

The Results show that the drug release rate by exposure across from a high temperature was significantly reduced, probably through a tablet hardening effect by exposure of the formulation to a temperature close to Softening point of the polymer.

Example 3

In Example 3, the tablets were in the same manner as prepared in Example 1. The ingredients of the tablets, prepared in Example 3 are shown in Table 5 below:

Table 5

As soon as The tablets of Example 3 were prepared, the release tests performed according to the method, as described in Example 1 performed. The release results are listed in Table 6 below:

Table 6

The Results show that the release rate of the tablets of Example 3 were faster than the targeted release rates, which were provided in Example 1. This was expected and is due to the reduced amount of excipients that have been used due. The Tablets of Example 3 were placed in a 50 ° C oven for 1.5 hours, 4 hours, 3 Placed days, 6 days and 10 days. The release results are as listed in Table 7 below.

Table 7

It it has been observed in the above examples that the drug release rate was reduced with increasing storage time, especially when they under increased Temperatures were stored. By curing the tablets at elevated temperatures (e.g., 50 ° C) for e.g. 4 hours, the drug release rate of tramadol from the hydrophobic material during significantly delayed in production and was over the time is stable under different storage conditions. The The above results show that the drug release rate of hardened Tablet with increasing curing time decreasing and stable in terms of drug release rates, the next Time were recorded, i. after three days. Under the assumption, that the release results close to the tablets of Example 1 at the desired Drug release rate, it is obvious that after coating and storage under ambient temperatures, release gradually reduced. To this instability in the Drug release rate with the storage time was prevented a new formulation with a faster than goal set Release (Example 3). The tablets were stored at 50 ° C for 1-3 days, to promote polymer coalescence in the matrix (curing) and to provide the desired release profile deliver.

This example also shows that because curing can slow the release to a stable endpoint, one can also use curing as a method to aid release delay so that less hydrophobic (retarding) adjuvants can be used NEN. This aspect of the invention is particularly important for relatively high-dose drugs such as tramadol, in that it can reduce the size of the final unit dose (eg, tablet) relative to the uncured product.

Example 4

The lubricated granulation used in the preparation of Example 3 were used to Example 4 in larger quantities manufacture. The tablets were further film-coated according to the method, as described in Example 1, and cured at 50 ° C for 1, 2, 3, 6 and 9 days. The Release results are listed below in Table 8:

Table 8

The Results, as shown in Table 8, show that curing for a Period of one day at 50 ° C is sufficient to allow the tablets to a stable end point harden (in which the drug release rate of the active ingredient of the formulation unchanged is opposite after exposure accelerated storage conditions). A cure period of up to 9 Changed days the release profile of the tramadol of the cured tablets was not significant.

The Tablets at 50 ° C for 3 days hardened were tested at the stability test at 25 ° C / 60 % relative humidity and 40 ° C / 75 % relative humidity for 1 and 3 months suspended. The release results are as follows shown in Table 9:

Table 9

Compared to the initial release data, the stability results show that the tablets, once cured, have stable release characteristics in numerous storage conditions and Have periods.

Example 5

In Example 5 was a different formulation containing a similar Wax (cetostearyl alcohol) to that which in the above examples was used and polymer produced. The wording was made according to one alternative methods as described in the description. The Close the tablets of example 5 the ingredients and amounts as shown in Table 10 below, with delayed tablets To produce release:

Table 10

Surelease is a watery Dispersion of ethyl cellulose, the dibutyl sebacate as plasticizer contains.

The Formulation was prepared by spraying the Surelease dispersion to a tramadol HCl / lactose mixture in a fluidized bed dryer ("fluid bed dryer"); Mix the melted Cetostearylalcohols in the granules in a high-mix mixer Shear force; Pass the mixture through a sieve and mix with Talk; Lubricate the resulting material with magnesium stearate and pressing the lubricated granules into tablets.

release test (carried out according to example 1) gave the following results, which are shown in Table 11:

Table 11

From the results shown in Table 11 can be seen that the tramadol release rate of this tablet formulation, which was made with other excipients and another Method of preparation (compared to Example 1-4) as well shows a slowdown after storage at high temperatures. Therefore can The formulations are stabilized by having the final product a hardening step, as described above.

Example 6

In Example 6, another different formulation was prepared, which contains another waxy material (hydrogenated vegetable oil) compared with that used in the above examples. It was no hydrophobic polymer incorporated as part of the hydrophobic material. The formulation was prepared according to an alternative method as described in the description. Tablets of example Close 6 the ingredients and amounts as shown in Table 12 below, to obtain controlled release tablets:

Table 12

The Tablets were prepared as follows. The tramadol HCl and the hydrogenated oil were placed in a bowl of mantle and mixed until melting and granulation occurred. The granulated material was then on transferred a metal tray and cooled to 42 ° C. A suitable grinding tool was then used to grind the granulated material. The milled material was then returned to shell with mantle and mixed until melt pelletization occurred. The resulting Pelleted material was passed through a 2 mm sieve and then through sieved a 0.5 mm sieve and the fraction of 0.5-2 mm particles (granules) was kept. The granules were then mixed with talc and lubricated with magnesium stearate, the resulting lubricated Granules were pressed into tablets.

• * Tablettenhärte = 5kp

The tablets of Example 6 were then subjected to release tests in accordance with the procedures described in Example 1. The results are shown in Table 13 below: Table 13

• * Tablet hardness = 5kp

The Formulation of Example 6 represents an in vitro drug release profile ready, which indicates that the final product, on a once-daily basis can be administered. After storage at 50 ° C for 3 days the drug release rate of the tablets decreased Example 6, however.

Example 7

There Example 4 in a small amount (less than 1 kg batch size) In Example 7, a larger batch ("scale-up lot") became similar in a similar manner Way with a larger extruder produced. In Example 7, however, the tablets were at 50 ° C for 24 hours hardened before coating. After this the curing step finished, the tablets were made using a drinking trough ("coating pan") (AccelatCota 48''pan) up to a weight gain of 4% using Opadry Beige under the following conditions film-coated: inlet temperature: 50-56 ° C; Outlet temperature: 38 40 ° C; Spray rate = about 200 ml / min .; Air flow: 2100-2400 cfm; atomizing air pressure: 65 psi.

The Release dates of the newly prepared cured tablets (initial or "time zero") and tablets, in room conditions (25 ° C / 60 % RH) and accelerated storage ("load") conditions (40 ° C / 75% RH) were stored, were in accordance with the method as described in Example 1 performed. The Results are shown in Table 14 below.

Table 14

The Results show that the release rate of the cured tablets is stable after storage under different conditions. Therefore can the formulations, as described above, in that the final product a hardening step is subjected to stabilized. It should be mentioned that these tablets were cured before coating. The tablets in the previous examples were coated before curing. The result shows that hardening makes no difference before or after the coating process.

To evaluate the steady state bioavailability of the formulations of Example 7, a multi-dose, three-way crossover study was performed on 24 normal volunteers. These subjects received 50 mg of Ultram ^™ (Tramadol immediate release tablets, commercially available from Johnson & Johnson) every 6 hours or once a day. Venous blood samples were taken for 24 hours at predetermined times on the 5th day. 1 shows the mean plasma tramadol concentration (ng / ml) over 24 hours on the 5th day after multiple dosing.

table 15 summarizes the pharmacokinetic parameters (arithmetic mean) of Tramadol on the 5th day after multiple doses of Ultram and Example 7 together.

Table 15

Example 8

Previous Examples show that sustained-release tramadol formulations, containing stearyl alcohol and ethylcellulose (hydrophobic polymer), a hardening effect (Release delay) after facing exposure 50 ° C temperature for 24 Hours showed. Example 8 uses a tramadol formulation delayed Release containing stearyl alcohol and no hydrophobic polymer, prepared, to determine if the hardening effect occurs when only stearyl alcohol is used.

The Tablets of Example 8 were prepared as follows. First became Stearyl alcohol provided in a stainless steel beaker and melted on a hot plate. Tramadol HCl was in a Hobart mixer placed. The molten stearyl alcohol was added to the tramadol Hcl powder while tilted the blend sheet was rotated. The mixture was allowed to solidify and cool to room temperature. The mixture was ground and talc and magnesium stearates. The lubricated granules was at 5-6 pressed in tablets. The tablets were placed in a 50 ° C oven for 24 hours hardened. The ingredients / amounts for the tablets of Example 8 are listed in Table 16:

Table 16

The Tablets of Example 8 were then made consistent in release assays subjected to the procedures of Example 1, both before curing and after hardening at 50 ° C for 24 Hours. The results are described in Table 17 below:

Table 17

One hardening was observed after the tablets were cured. The extent of the release delay was but not as significant as in the previous examples. Even though the invention is shown in relation to the particular formulations in which a sustained release tramadol formulation was prepared which includes a wax or waxy material softened or melted during the preparation of the dosage form, the skilled person will recognize in the pharmaceutical formulation, that many other processes for the preparation of matrix formulations, in which the wax or waxy materials (or a material, which is like a wax or a wax-like material in the softens, melts or was heated to a temperature above its glass transition temperature, be useful in the preparation of the formulations according to the invention becomes. Furthermore, the person skilled in the pharmaceutical formulation acknowledge that the time and temperature that is necessary to order a curing endpoint, as defined herein may vary depending on the specific ingredients and amounts thereof, which are specific in each Formulation are included. It will also be in certain situations possible be the curing temperature raise and cure time lower and vice versa.

Claims (24)

A stabilized solid oral dosage form with delayed Release comprising tramadol as active ingredient, comprising an effective Amount of tramadol or a pharmaceutically acceptable salt thereof, dispersed in a matrix of a hydrophobic material, comprising a wax-like Substance that during the preparation of the matrix has been melted or softened, wherein the solid dosage form at a temperature of 35 ° C to 65 ° C for a sufficient Time hardened so that an endpoint is reached at which the solid dosage form provides a stable release profile, the endpoint by comparing the release profile of the solid dosage form right after curing with the release profile of the solid dosage form after they accelerated storage conditions of at least one month at 40 ° C and 75% relative humidity is determined. The stabilized solid oral dosage form with delayed A release according to claim 1 wherein said curing is at a temperature of 40 ° C to 60 ° C for a period of time from 4 to 72 hours becomes. The stabilized solid oral dosage form with delayed A release according to claim 1 wherein said curing is at a temperature of 45 ° C to 55 ° C for a period of time from 4 to 72 hours becomes. The stabilized solid oral dosage form with delayed Release according to claims 1-3, where the hardening for one Time span of 24 hours is carried out. The stabilized sustained-release solid oral dosage form of claims 1-4, wherein the wax-like substance is selected from the group consisting of hydrogenated vegetable oil, hydrogenated castor oil, Paraffin, higher aliphatic alcohols, higher aliphatic acids, long chain fatty acids, fatty acid esters and mixtures thereof. The stabilized solid oral dosage form with delayed Release according to claims 1-5, where the hydrophobic material furthermore a hydrophobic polymer selected from the group consisting of acrylic polymers, alkylcelluloses and mixtures of which includes. The stabilized solid oral dosage form with delayed Release according to claims 1-6, continue comprising a hydrophilic polymer. The stabilized solid oral dosage form with delayed Release according to claims 1-7, where the hydrophilic polymer is a cellulose ether. The stabilized solid oral dosage form with delayed Release according to claims 1-4, where the Matrix Tramadol, a higher aliphatic alcohol and a hydrophobic polymer selected from the group consisting of acrylic polymers, alkylcelluloses and mixtures of which includes. The stabilized solid oral dosage form with delayed Release according to claims 1-4, where the Matrix tramadol and hydrogenated vegetable oil includes. The stabilized solid oral dosage form with delayed Release according to claims 1-10, which is a tablet. The stabilized solid oral dosage form with delayed Release according to claims 1-11, which releases an amount of tramadol that does not give rise to any Release time by more than about 20% of the total at this release date released tramadol when differentiated with in vitro release compared with the accelerated storage conditions carried out has been. The stabilized solid oral dosage form with delayed A release according to claim 6, wherein the hydrophobic polymer is from about 0 wt .-% to about 80 wt .-% of the hydrophobic material. The stabilized solid oral dosage form with delayed A release according to claim 6, wherein the hydrophobic polymer is from about From 30% to about 50% by weight of the hydrophobic material. A method for producing a stabilized solid oral sustained-release dosage form containing Tramadol as an active ingredient, comprising, Producing a matrix, comprising tramadol or a pharmaceutically acceptable salt thereof, dispersed in a matrix of a hydrophobic material, comprising a wax-like Substance, being the wax-like substance while the preparation of the matrix is melted or softened, and thereafter Hardening the Matrix at a temperature of 35 ° C to 65 ° C for a sufficient time, so an end point is reached at which the matrix becomes a stable one Release profile, the endpoint by comparing the release profile of the matrix directly after curing with the release profile of the matrix after accelerated storage conditions for at least one month at 40 ° C and 75% relative humidity is determined. The method of claim 15, wherein it further compressing the matrix into a tablet. The method of claim 16, wherein the tablets by feeding the tramadol and the hydrophobic material, optionally together with other pharmaceutical excipients, in an extruder at temperatures that are high enough to be waxy Material to soften or melt, extruding the mixture, Granulating the mixture, lubricating of the granules and then compressing the granules in tablets become. The method of claim 16, wherein the tablets are prepared by spraying a hydrophobic polymer dispersion onto a mixture of tramadol and an inert diluent in a fluid bed dryer to obtain granules, mixing molten wax-like substances into the granules in a high shear mixer "), Passing the mixture through a sieve and mixing with talc, lubricating the resulting material and compressing the lubricated granules in Tab be represented. The method of claim 16, wherein the tablets by pouring the molten wax-like Substance on the tramadol in a pharmaceutically suitable blender, Allow to solidify and allow to cool mixing and then grinding the mixture, lubricating mixing and compressing the lubricated granulation be presented in tablets. The method of claim 16, wherein the tablets by melting and granulating a waxy substance, hydrating of a cellulose ether and granulating the same, blending the tramadol either with the granulated melt, the granulated cellulose ether, or a mixture thereof, drying the granules and then optionally Mix with a suitable amount of a pharmaceutically acceptable inert diluent and compressing the mixture into tablets getting produced. The method of claim 16, wherein the hydrophobic Material a hydrophilic or hydrophobic polymer in addition to the wax-like Substance comprises, and the tablets by (a) wet granulation of the hydrophobic or hydrophilic polymer and optionally diluent with or without tramadol, (b) drying and classifying the resulting granules; (c) combining the tramadol with the granules, if not previously in step (a), incorporate the wax-like substance in the molten one Condition in the granules using a suitable mixer, (d) cooling and classifying the granules and then (e) lubricating granules, compressing the lubricated granules in tablets being represented. The method of claims 15-21, wherein curing a temperature of 40 ° C up to 60 ° C for a period of time from 4 to 72 hours becomes. The method of claims 15-21, wherein curing a temperature of 45 ° C up to 55 ° C for a period of time from 4 to 72 hours becomes. The method of claims 15-21, wherein said curing is for a period of time carried out for about 24 hours becomes.